Enteric-coated proliposomal formulations for poorly water soluble drugs

ABSTRACT

This invention relates to enteric-coated proliposomal formulations for oral medicaments. In particular, it relates to an enteric-coated proliposomal oral drug delivery system for poorly water soluble drugs and methods for making the same. The drug delivery system comprises a pharmaceutical agent, a phospholipid and an enteric coating material. The present invention provides enhanced stability and bioavailability for orally administered drugs.

RELATED APPLICATIONS

This application claims benefit to U.S. Provisional Application No.60/286,386, filed April 25, 2001, the entire teachings of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to enteric-coated proliposomal formulations fororal medicaments. In particular, it relates to enteric-coatedproliposomal formulations for poorly water soluble drugs.

2. Description of the Related Art

Among the various routes of drug administration, the oral route ispreferred because of its versatility, safety and patient comfort. Theencapsulation of pharmaceuticals in liposomes is useful in reducingtoxicity and improving the therapeutic effectiveness of certain drugs.For example, compounds such as insulin, factor VIII, tryptophan,phenylalanine, heparin, vitamin K etc., have been investigated for theireffectiveness orally, after encapsulation into liposomes. Although theyrepresent an improvement over the prior art, oral liposome formulationshave been criticized because of their instability, leakage and potentialdestruction in gastric fluids.

The use of proliposomes represents an alternative to conventionalliposomal formulations. Proliposomes are dry, free-flowing granularproducts, which, upon the addition of water, disperse to form amultilamellar liposomal suspension. The stability problems associatedwith conventional liposomes, including aggregation, susceptibility tohydrolysis and oxidation, may be avoided by using proliposomes. The useof proliposomes is well known in the pharmaceutical field.

Although the oral ingestion of drugs represents a safe and versatilemethod of pharmaceutical delivery, the therapeutic efficacy of manydrugs is reduced because many pharmaceuticals are labile or inactivatedunder the acidic conditions of the stomach. Enteric coating materialshave been applied to address this deficiency. Enteric coating materialsare those that ensure that acid-labile drugs remain active in thestomach upon oral ingestion such that the active ingredient is releasedand absorbed in the intestine. Enteric coatings materials are well knownin the pharmaceutical art and include alginates, alkali-soluble acrylicresins, hydroxypropyl methylcellulose phthalate, cellulose acetatephthalate, and the like.

Although the use of proliposomes and the use of enteric coatings areindependently known in the art, the combination of an enteric coatingwith a proliposomal formulation has not been disclosed. Surprisingly,when an enteric coating of the current invention is combined with aproliposomal formulation of the current invention, drug delivery isenhanced. In many embodiments of the present invent, this novel andunexpected enhancement, which results from the unique combination of anenteric coating and a proliposomal formulation, relates to increaseddrug absorption, stability and bioavailablity.

In many embodiments of the current invention, the combination of anenteric coating and a proliposomal formulation overcomes thedisadvantages of drug delivery systems known in the prior art. Forexample, the utility of previous systems for orally administering labilepharmacological substances has been limited by the need to use toxicamounts of delivery agents, the instability of the systems, theinability to protect the active ingredient, the inability to effectivelydeliver drugs that are poorly water soluble or labile, the inadequateshelf life of the systems, the failure of the drug delivery systems topromote absorption of the active agent and the difficulties inherent tomanufacturing the systems.

SUMMARY OF THE INVENTION

The current invention relates to a drug delivery system comprising atleast one pharmaceutically active agent, at least one phospholipid andan enteric coating material. A particular advantage of the currentinvention is that it provides a simple and inexpensive system tofacilitate the oral administration of medicaments. In many embodiments,this drug delivery system enhances the stability and bioavailability ofpharmaceutically active agents.

In one aspect of the invention, the pharmaceutically active agent is apoorly water soluble drug.

In another aspect of the invention, the phospholipid is distearoylphosphatidylcholine, dipalmitoyl phosphatidylcholine or dimyristoylphosphatidylcholine and the enteric coating material is celluloseacetate phthalate.

In another aspect of the invention, a pharmaceutical formulation isdelivered in a tablet, capsule, suspension and/or liquid form. Inalternative embodiments, carriers, diluents and/or lubricants are alsoincluded in the pharmaceutical formulation.

Another aspect of the invention relates to a method for making the drugdelivery system comprising combining at least one pharmaceuticallyactive agent with at least one phospholipid, and thereafter coating thecombination with an enteric coating material. In alternate embodiments,pharmaceutically inactive agents, such as carriers, diluents andlubricants, are also included in the drug delivery system. Placebo mayalso be delivered according to certain embodiments of the invention.

A further aspect of the invention relates to a method for delivering apharmaceutical formulation to a mammal by orally administering theformulation to the mammal. In specific embodiments, the currentinvention relates to preventing, diagnosing or treating an illness in amammal with the drug delivery system of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a comparison among dissolution rates of testosterone usingvarious proliposomal formulations and pure testosterone.

FIG. 2 shows a comparison between dissolution rates of famotidine usinga proliposomal formulation (DSPC) and pure famotidine.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Several embodiments of present invention relate to enteric coatedproliposomal formulation comprising a pharmaceutically active agent, aphospholipid and an enteric coating material. In preferred embodiments,the enteric coated proliposomal (EnProLip™) formulation enhances thedissolution and bioavailability of drugs. The effect is more pronouncedfor drugs with extremely low water solubility, such as halofantrine andtestosterone. A less pronounced rate of dissolution is observed withdrugs with higher water solubilities, such as famotidine. In oneembodiment, the current invention consists of a drug delivery systemwhich provides a more rapid onset of drug action, a longer duration ofaction and an increased C_(max) as compared to administration of thedrug alone.

In a preferred embodiment, the formulation comprises

(a) a poorly water soluble drug;

(b) distearoyl phosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC) or dimyristoyl phosphatidylcholine (DMPC);and

(c) cellulose acetate phthalate.

In one embodiment, the pharmaceutically active agent is a poorly watersoluble drug. Poorly water soluble drugs are pharmaceutically activeagents which require greater than approximately thirty (30) parts ofsolvent per one (1) part of solute to dissolve. Examples of poorly waterdrugs include, but are not limited to, griseofulvin, famotidine,meclizine, cyclosporine, carbamazipine, methotrexate, itraconazole,dipyridamole, mercaptopurine, halofantrine, amiodarone, lomustine,testosterone, misoprostil, etoposide, rifamycin, azathioprine,glyburide, tolbutamide, aminoglutethimide, taxol, clofibrate,nifedipine, methyldopa, ramipril, dicumarol, and the like. One skilledin the art will appreciate that this invention is not limited to poorlywater soluble drugs but includes a wide range of pharmaceutically activeand inactive agents. Drugs that are slightly soluble, sparingly solubleor hydrophilic may also be delivered using various embodiments of thepresent invention.

In a preferred embodiment, DSPC, DPPC or DMPC is used as thephospholipid. One skilled in the art will understand that otherphospholipids, including, but not limited to, egg PC, soy PC, DMPG,DMPA, DPPG, DPPA, DSPG, DSPA, phosphatidylserine, sphigomyelin, and thelike may be used.

In a preferred embodiment, cellulose acetate phthalate is used as theenteric coating. However, one skilled in the art will appreciate thatalginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulosephthalate, methacrylate-methacrylic acid coplymers, polyvinyl acetatephthalate, styrol maleic acid copolymers and the like may also be used.One skilled in the art will also appreciate that the enteric coatingmaterial used in various embodiments of the invention may include acombination of the aforementioned coatings.

In one embodiment of the invention, the enteric coated proliposomedelivery system will be used for anti-emetic purposes by preventing therelease of noxious ingredients in the stomach, thereby reducing nauseaand other adverse side effects.

In another embodiment of the invention, the enteric coated proliposomalformulation is used to deliver drugs which are susceptible todegradation in the intestinal tract.

In another embodiment, the current invention will be used to administerdrugs through various routes. The present invention will also be used toenhance delivery of drugs or other substances in the food industry,where enzyme immobilization is essential for various aspects of foodprocessing.

In a further embodiment, the current invention will be used to treat amammal comprising administering to the mammal a pharmaceutically activeagent, a phospholipid and an enteric coating material.

One skilled in the art will understand that the current invention is notlimited to the delivery of drugs or pharmaceutical agents. Any number ofnaturally occurring or synthetic substances, including diagnostic agentsand therapeutic materials, may be delivered according to the currentinvention. These substances include, but are not limited to, anorexics,analgesics, antiarthritics, adrenergic blocking agents, steroids,vaccines, peptides, proteins, hormones, antibodies, antibiotics,antiviral agents, vitamins, nucleotides, nutritional agents, enzymes,genes, genetic material, cytotoxins, bacteria, microbes, viral agents,and the like. Placebo may also be administered using various embodimentsof the current invention. Diluents, carriers, lubricants and the like,including, but not limited to, microcrystalline cellulose, starch,lactose, talc, mannitol, polyethylene glycol, polyvinylpyrrolidone,hydroxypropylmethyl cellulose, ethyl cellulose, fatty acids, fatty acidsalts, glyceryl behenate, dextrose, dicalcium phosphate may also beadministered using several embodiments of the present invention.

Further, one skilled in the art will understand that the amount of theactive pharmaceutical or substance used in the current invention willdepend on the dose required to be administered and the treatmentdesired. One skilled in the art will appreciate that “treatment” refersto any desired purpose for administering the pharmaceutically activeingredient, including prevention, control, cure, maintenance orimprovement of health, and the like. By varying the concentration of theingredients, size, number and/or amount of tablets, capsules, suspensionor liquid, a wide range of doses may be orally administered.Time-released drugs may also be administered according to variousembodiments of the present invention.

One skilled in the art will also appreciate that the current inventionis not limited to the delivery of a single pharmaceutical agent. Indeed,more than one pharmaceutical agent may be delivered simultaneously usingthe current drug delivery system. For example, in one “dose”, therecipient may receive a combination of two or more drugs, at least onedrug and a carrier, etc.

In one embodiment of the invention, the drug delivery system issynthesized in the following manner: At least one pharmaceuticallyactive agent and at least one phospholipid are dissolved in solvent atappropriate ratios and concentrations. Upon dissolution, the solvent isevaporated to yield a dry powder-like material. The dried material ispassed through a sieve-like apparatus. This dried material is thencoated with an enteric coating, which is preferably in solution and canbe sprayed onto the dried material. The coated particles are then usedto synthesize tablet, capsule or liquid preparations suitable fordelivery to a mammal.

Several embodiments of the current invention are particularlyadvantageous because they allow for the enteric coating to be appliedafter the pharmaceutically active agent and phospholipid are mixed. Thispermits preparation of different forms of the formulation, including,tablets, capsules, suspensions, or liquids. Moreover, various embodimentof the present invention allow for the facile preparation of tablets ofvarious sizes. The size of the tablets is preferably controlled byadjusting the pore size of the mesh or sieve.

I previously described a method for preparing drugs in a tablet orcapsule form with an enteric coating. However, a particular advantage ofvarious embodiments of the current invention is the ability to generatesuspension or liquid forms of the formulation. Suspension or liquidforms are sometimes preferable because they do not affectgastrointestinal motility to the same extent as do capsules or tablets.For most drugs, it is important that that the pharmaceutically activecompound is not eliminated in the gastrointestinal tract before it hashad a chance to exert a localized effect or to pass into thebloodstream. When a formulation is in a suspension or liquid form, it istypically retained in the intestine for longer periods of time and, assuch, absorption is increased as compared to capsules or tablets.Various aspects of this invention also provide for flexibility in thesurface area of the formulation. Whereas tablets are generallyrestricted to a fixed surface area, several embodiments of the presentinvention permit the use of capsules, suspensions and liquids, which mayprovide a larger surface area and hence contribute to increasedabsorption and bioavailability.

I previously described a method for delivering drugs in which the drugwas exposed to an aqueous phase. According to several embodiments of thecurrent invention, the lipid and the drug are exposed to chloroform, orsimilar solvent. There is no exposure to an aqueous phase. For watersensitive drugs and drugs that are labile in water, such as antibodies,the absence of an initial aqueous phase preserves the integrity of thesedrugs. Further, because there is no exposure to an aqueous phase,liposomes are not formed. Hence, several embodiments of the currentinvention are directed to non-liposomal pharmaceutical formulations. Asused herein, “non-liposomal” is defined as a formulation which is notexposed to an aqueous phase, and thus does not form liposomes, prior tothe application of the enteric coating.

Not wishing to be bound by the following description, it is believedthat various embodiments of the current invention work in the followingmanner: After formation of the proliposome formulation, the formulationis orally delivered to a mammal. When the proliposome formulationencounters an aqueous phase at a pH at or above approximately 7.0,liposomes are formed and the drug molecules are transported across thegastrointestinal membrane.

The following Examples illustrate various embodiments of the presentinvention and are not intended in any way to limit the invention.

EXAMPLE 1

Halofantrine and distearoyl phosphatidylcholine (1:3 ratio) weredissolved in chloroform and the solvent was evaporated using nitrogengas. The dry powder was passed through a # 60 mesh screen. Celluloseacetate phthalate (50 mg) was dissolved in acetone (6 ml) and sprayed onthe halofantrine and distearoyl phosphatidylcholine mixture.

Dissolution was carried out using 40 mg of the formulation using a TypeII USP dissolution apparatus. The dissolution medium (250 ml) wasphosphate buffered saline (pH 7.4). The temperature of the dissolutionmedia was maintained at 37 ±0.5° C. and the rotation of the paddle wasset at 50 rpm. Samples (5 ml) were withdrawn at 5, 10, 15, 30, 45, 60,90, 120, 180 and 240 minutes. Equal volumes of phosphate buffered salinewere added to maintain a constant volume of dissolution media.

The samples were analyzed by high performance liquid chromatography(HPLC). In the mobile phase, 46.5:53.5 (0.025 M potassiumphosphate/sulfuric acid/triethylamine solution):acetonitrile wascombined, mixed and filtered using a Kontes filter apparatus. Sodiumdodecyl sulfate (1.1 g/L of mobile phase) was added to the filteredsolution.

The parameters of the assay procedure was as follows. The flow rate wasset at 1.2 ml/minute. The temperature was ambient. The run time was 30minutes. The ultraviolet light detector was set at a wavelength of 254nm. The retention times for (+) halofantrine and (−) halofantrine were25 minutes and 28 minutes respectively.

The pharmacokinetic parameters of the enteric coated proliposomalformulation of halofantrine were evaluated as follows. The proliposomalproduct was prepared as a suspension in 0.78% methylcellulose. Anon-liposomal suspension formulation (control) was prepared bydispersing halofantrine powder in 1% methylcellulose. Sprague-Dawleyrats were cannulated at the right jugular vein under halothaneanesthesia. After an overnight rest, the rats were given 7 mg/kg of ahalofantrine suspension as either the proliposomal (7 rats) or control(6 rats) formulation by oral gavage. Serial blood samples were obtainedfrom the cannula until 48 h post-dose. A stereospecific HPLC assay wasused to measure plasma concentration of halofantrine enantiomers.Noncompartmental pharmacokinetic methods were used to determine AUC₀₋₂₄,C_(max) and t_(max). Student's unpaired t-test was used to assesssignificance of differences. Results (mean±SD) are provided in Table 1.

TABLE 1 Pharmacokinetic Results of the Halofantrine Study AUC, μg × h/mLCmax, ng/mL Tmax, h Control Liposome Control Liposome Control Liposome(+)-HF 5.2 ± 7.7 ± 391 ± 722 ± 7.0 ± 4.1 ± 0.81^(b) 1.8^(a,b) 59.2^(b)170^(a,b) 2.8 2.3 (−)-HF 1.9 ± 2.6 ± 196 ± 360 ± 4.6 ± 4.0 ± 0.530.66^(a) 42.3 80.5^(a) 2.1 1.3 ^(a)= p < 0.05 compared to control; ^(b)=p < 0.05 compared to antipode

The proliposomal formulation displayed higher bioavailability of bothenantiomers than did the control formulation. The AUC and C_(max) ofhalofnatrine enantiomers increased by over 40% and 80%, respectively.Although the mean tmax was lower for both enantiomers in theproliposomal formulation, the differences from control were notstatistically significant.

EXAMPLE 2

Testosterone and phospholipid (DMPC, DPPC or DSPC; 1:1 ratio) weredissolved in chloroform. Chloroform was evaporated using nitrogen gas.The dry powder was passed using a # 60 mesh sieve. Cellulose acetatephthalate (40 mg) was dissolved in acetone (5 ml) and the resultingsolution was sprayed on the solid dispersion containing the testosteroneand phospholipid. Nitrogen gas was used to dry the powder.

Dissolution was carried out using 45 mg of the formulation using a TypeII USP dissolution apparatus. The dissolution medium (300 ml) wasphosphate buffered saline (pH 7.4). The temperature of the dissolutionmedia was maintained at 37 ±0.5° C. and rotation of the paddle was setat 50 rpm. The samples (5 ml) were withdrawn at 2, 5, 8, 10, 15, 20, 25,30, 40, 50, 60, 80, 100, and 120 minutes. Equal volumes of phosphatebuffered saline were added to maintain a constant volume of dissolutionmedia. Dissolution samples were analyzed by measuring the absorbance at254 nm.

The rate and extent of dissolution of testosterone was significantlygreater with all proliposomal formulations as compared to puretestosterone as shown in FIG. 2. The extent of dissolution was highestwith the proliposomal formulation containing DMPC, followed by DSPC andDPPC. This may be explained by the phase transition temperature (Tc) ofthese lipids. DPPC has a Tc of 41° C., which is very close to thetemperature of the dissolution study (37° C.). DMPC and DSPC have Tc'sof 23° C. and 56° C. respectively. DMPC exists in a fluid state and DSPCin a gel state at 37° C. Because the Tc of DPPC was similar to thetemperature of the dissolution study, the formulation may have beenunstable, thus hampering the dissolution of testosterone. Nonetheless,the data indicates that the rate and extent of dissolution oftestosterone was increased by using the enteric coated proliposomalformulation.

EXAMPLE 3

Famotidine and distearoyl phosphatidylcholine (DSPC; 1:3 ratio) weredissolved in chloroform. Chloroform was evaporated using nitrogen gas.The dry powder was passed using a # 60 mesh sieve. Cellulose acetatephthalate (50 mg) was dissolved in acetone (5 ml) and the resultingsolution was sprayed on the solid dispersion containing testosterone andphospholipid. Nitrogen gas was used to dry the powder.

Dissolution was carried out using 87 mg of the formulation using a TypeII USP dissolution apparatus. The dissolution medium (300 ml) wasphosphate buffered saline (pH 7.4). The temperature of the dissolutionmedia was maintained at 37 ±0.5° C. and the paddle rotation was set at50 rpm. The samples (5 ml) were withdrawn at 2, 5, 8, 10, 15, 20, 25,30, 40, 50, 60, 80, 100, and 120 minutes. Equal volumes of phosphatebuffered saline were added to maintain a constant volume of dissolutionmedia. Dissolution samples were analyzed by measuring the absorbance at285 nm.

The rate of dissolution of famotidine formulation was significantlygreater than pure famotidine. However, there was no significant increasein the extent of dissolution of famotidine in PBS. Because theproliposomal formulation results in a faster rate of dissolution, theonset of drug action will be more rapid.

While a number of preferred embodiments of the invention and variationsthereof have been described in detail, other modifications and methodsof use will be readily apparent to those of skill in the art.Accordingly, it should be understood that various applications,modifications and substitutions may be made of equivalents withoutdeparting from the spirit of the invention or the scope of the claims.

What is claimed is:
 1. A method of making a granular pharmaceuticalproduct consisting essentially of: combining at least one lipophilicpharmaceutically active agent with at least one phospholipid in anon-aqueous solvent wherein said pharmaceutically active agent is apoorly water soluble drug; evaporating said non-aqueous solvent toproduce a powder; and applying an enteric coating material to saidpowder to produce a granular product, wherein said enteric coating is incontact with at least a portion of said powder; and forming said coatedgranular product into a dosage form selected from the group consistingof one or more of the following: a capsule, suspension and tablet. 2.The method of claim 1, wherein said pharmaceutically active agent isselected from the group consisting of one or more of the following:famotidine, halofantrine, testosterone, and glyburide.
 3. The method ofclaim 1, wherein said phospholipid is a pliosphatidyl phospholipid. 4.The method of claim 1, wherein said phospholipid is selected from thegroup consisting of one or more of the following: distearoylphosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoylphosphatidylcholine, egg PC, soy PC, DMPG, DMPA, DPPG, DPPA, DSPG, DSPA,phosphatidylserine and sphigomyelin.
 5. The method of claim 1, whereinsaid enteric coating material is selected from the group consisting ofone or more of the following: cellulose acetate phthalate, alginates,alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate,methacrylate-methacrylic acid coplymers, polyvinyl acetate phthalate andstyrol maleic acid copolymers.
 6. The method of claim 1, wherein saidapplying an enteric coating material comprises spraying said powder withsaid enteric coating material.
 7. A method for delivering thepharmaceutical formulation produced by the method of claim 1 to a mammalcomprising orally administering said granular pharmaceutical product tosaid mammal.
 8. A method for diagnosing or treating an illness in amammal comprising administering the granular pharmaceutical productproduced by the method of claim
 1. 9. The method of claim 8, whereinsaid granular pharmaceutical product is administered at a biologicallyactive dose.
 10. The method of claim 8, wherein said granularpharmaceutical product forms liposomes in the mammal's gastrointestinaltract.